Treatment of ophthalmic conditions

ABSTRACT

Ophthalmic conditions such as presbyopia, myopia, and astigmatism can be corrected by the use of a molding contact lens in combination with a pharmaceutical composition suitable for delivery to the eye. The molding contact lenses are preferably commercially available and are not specifically designed for orthokeratology. The agents in the pharmaceutical compositions such as hyaluronase allow the cornea of the eye to be molded in order to correct the refractive error of the eye. The contact lenses and the pharmaceutical composition induce a change in the radius of curvature of the anterior surface of the cornea, thereby correcting the refractive error of the eye. One advantage of the inventive technique is that the patient with his or her own individual visual needs guides the treatment until the patient near and far visual needs are met. The present invention also provides for kits, which contain molding contact lenses, pharmaceutical composition suitable for delivery to the eye, and instructions, useful in the inventive system.

PRIORITY INFORMATION

The present application is a continuation of and claims priority under35 U.S.C. § 120 to U.S. patent application Ser. No. 15/004,246, filedJan. 22, 2016, which is a continuation of and claims priority under 35U.S.C. § 120 to U.S. patent application Ser. No. 14/532,851, filed Nov.4, 2014, now issued U.S. Pat. No. 9,241,980, which is a divisional ofand claims priority under 35 U.S.C. § 120 to U.S. patent applicationSer. No. 14/223,130, filed Mar. 24, 2014, now issued U.S. Pat. No.8,877,228, which is a continuation of and claims priority under 35U.S.C. § 120 to U.S. patent application Ser. No. 13/932,842, filed Jul.1, 2013, now issued as U.S. Pat. No. 8,679,521, which is a continuationof and claims priority under 35 U.S.C. § 120 to U.S. patent applicationSer. No. 10/582,728, filed Jun. 14, 2006, now issued U.S. Pat. No.8,475,831, which is a national stage filing under 35 U.S.C. § 371 ofinternational PCT application, PCT/US2004/042660, filed Dec. 17, 2004,which claims priority under 35 U.S.C. § 119(a) to Mexican patentapplication, No. PA/a/2003/011987, filed Dec. 19, 2003, entitled “MÉTODOPARA EL TRATAMIENTO DE LA PRESBICIA INDUCIENDO CAMBIOS EN EL PODER YFISIOLOGIA CORNEAL,” each of which is incorporated herein by reference.

FIELD OF THE INVENTION

The present invention provides a system for treating presbyopia, myopia,hyperopia, astigmatism, and other ophthalmic conditions by inducingchanges in the cornea of the eye, including the cornea's dioptric power.

BACKGROUND OF THE INVENTION

Of the four refractive interfaces of the eye, the anterior surface ofthe cornea provides most of the refractive power of the eye. Therefore,various surgical techniques have been developed which change thecurvature of the cornea in order to treat ophthalmic conditionsinvolving errors of refraction such as myopia and hyperopia. Thesetechniques include keratotomy, keratomileusis by a freezing process,automated lamellar keratomileusis (ALK), photo-reactive keratomileusis(PRK), laser-assisted in situ keratomileusis (LASIK), laser intrastromalkeratomileusis, laser epithelial keratomileusis (LASEK), conductivekeratoplasty (CK), and scleral resection (see published US PatentApplication 2003/0139737; U.S. Pat. No. 5,144,630; U.S. Pat. Nos.5,520,679; 5,484,432; 5,489,299; 5,722,952; 5,465,737; 5,354,331;5,529,076, 6,258,082; 6,263,879; each of which is incorporated herein byreference). All of these techniques work by using various techniques tochange the curvature of the cornea, but they are limited by how muchrefractive error can be corrected and the type of patients who can betreated using these techniques (e.g., in some patients the cornea is toothin to safely utilize techniques which would further thin the cornea).Some of the techniques involve making incisions in the cornea with adiamond knife and/or ablating areas of the cornea thereby increasing therisk of infection or other complications. These techniques also largelydepend on the dexterity of the surgeon performing the procedure, his orher surgical experience, and his experience performing laser ablations(e.g., with a Er:YAG (at 2.94 microns), Ho:YAG laser (at about 2microns); Raman-shifted solid state laser (at 2.7-3.2 microns), oroptical parametric oscillation (OPO) laser (at 2.7-3.2 microns).

Even more modern techniques are limited by their ability to cut cornealor sclera tissue with the desired precision causing a small, or evenmoderate, amount of refractive error to remain after the procedure andnot allowing one to achieve the desired vision for near and for far inone single surgical procedure. The remaining refractive error may alsobe irregular making it more difficult to correct in the future. When onecan not meet the visual demands that the patient requires, theophthalmologist must resort to additional methods to correct theremaining refractive error. This is usually done by prescribing eyeglasses, prescribing contact lenses, or performing a second surgicalprocedure (commonly known as a “retouch”). Therefore, limitations on thecorrection of refractive error using these techniques are significant,and the risk of having uncorrectable vision even with a secondarymeasure is considerable.

In addition, attempts to treat presbyopia using these techniques havealso had very limited success. Presbyopia, also known as short armsdisease, is a lack of lens accommodation, which prevents the eye fromchanging its focus. This phenomenon eventually occurs in all individualsover the age of forty. Accommodation allows an individual to see nearbyobjects by causing both eyes to converge on a near focal point, thepupil to shrink (myosis), and the lens to increase its dioptric power,thereby increasing its curvature in order to focus the image of nearbyobjects on the retina. Typically, young children have a totalaccommodation of 14 diopters. As a person ages, the lens of the eyebecomes larger, thicker, and less elastic. These changes in the lens arelargely due to the progressive denaturation of proteins in the lens. Asthe ability of the lens to change shape decreases, the power ofaccommodation decreases from approximately 14 diopters in young childrento less than 2 diopters at the age 45 to 50 and to about zero at age 70.Once a person reaches the state of presbyopia, the eye remains focusedpermanently at an almost constant distance, which is largely determinedby the physical characteristics of the individual's eye. The eye can nolonger accommodate to see both near and far requiring an older person towear bifocal glasses with the upper segment for seeing far and the lowersegment for seeing near.

This general view of accommodation and presbyopia also does not takeinto account other aspects of the visual system. For example, this viewdoes not take into account the higher cognitive functions necessary toorchestrate the eyes, the muscular system, and the brain including thevisual cortex in the process of accommodation. The monovision techniquesdescribed above (e.g., the myopization of one eye, LASIK monovision),the different techniques that cause positive areas in the central zoneof the cornea by making changes in the peripheral curvature, and thesclera resection or implants to change the scleral rigidity, cilliarymuscle, and zonule, and increase the accommodation power of the lensamong other more invasive techniques have had very limited success in,treating presbyopia. These disappointing results may stem from a varietyof sources including the lack of full understanding of the physiologicalbehavior of the eye and its connections with the brain, the nervoussystem, and the muscular system, the imprecise measurement of therefractive power of the cornea and lens, and the lack of precision insurgical techniques performed by human surgeons.

Ophthalmologists have begun to use sophisticated equipment to measurevarious parameters of the eye in order to treat presbyopia. However,even the most sophisticated measurements are just approximations due tothe fact that the cornea and other parts of the eye are similar to afingerprint in that there are numerous variations which cannot beadequately described by a finite set of parameters. Also, it isimpossible to precisely know how the cornea, lens, retina, and otherparts of the visual system will react after surgery under differentconditions (e.g., near and far visual stimuli). Furthermore, it isimpossible to know how the cornea will heal after refractive surgery(e.g., the final radius of curvature).

The limitations on the existing treatments of presbyopia stein from thefact that these techniques consider only one anatomical region of theeye (i.e., the cornea or the lens). Any correction of near vision inturn causes the far vision of the subject to diminish. In addition,these current techniques model the eye using, among others, Gullstrand'smodel of the eye which neglects the individuality and uniqueness of eachsubject's eyes. For example, the ocular globe is not a perfect sphere.Although there are many mathematical models of the eye and itscomponents used in calculating corneal power and the power of the globe(e.g., ray tracing), Gullstrand's model is probably the most popular.

Therefore, a need remains for a successful, non-invasive treatment ofpresbyopia. Presumably, this treatment could also be used to treat otherophthalmic conditions involving refractive errors including myopia,hyperopia, and astigmatism.

SUMMARY OF THE INVENTION

The present invention provides a system for treating ophthalmicconditions such as presbyopia, myopia, hyperopia, astigmatism, and otherconditions involving errors in refraction of the eye. The system altersthe corneal physiology, including the dioptric power of the cornea,through a dynamic and interactive technique which alters the shape ofthe cornea, thereby altering its refractive power. The patient beingtreated guides the treatment with respect to his or her visual needs,and the physician or optometrist uses this feedback from the patient aswell as information regarding the age of the patient, the patient'svisual needs (e.g., work habits, daily life), the patient's visualacuity, measurements of the eye, etc. to design the proper treatmentregimen. In this way, the individuality of each person being treated andhis or her eyes is taken into account during the treatment procedure.The treatment involves wearing a set of prescribed contact lenses toreshape the cornea and administering a pharmaceutical composition (e.g.,eye drops) formulated for the patient to allow for reshaping of thecornea.

One of the many advantages of this system is that changes in the corneaare made without utilizing any type of surgery. Another advantage overcurrent treatments is that the inventive system is dynamic, gradual, andinteractive; therefore, it can be adjusted or repeated as many times asnecessary to meet the visual needs of the patient. Also, the changesinduced in the cornea are reversible. For example, the technique mayneed to be repeated due to progression of the disease, changes in visualacuity, aging, changes in working habits, changes in reading habits,etc. Preferably, the visual needs of the patient are met with the firsttreatment.

First, to achieve fine adjustments in the curvature of the cornea,instruments are used to measure the refractive power of the cornea, thecurvature of the cornea, the thickness of the cornea, and the shape ofthe ocular globe (i.e., the total power of the eye). After these initialmeasurements are made and the change in curvature of the cornea to beinduced is determined, a set of contact lens is prescribed for use bythe patient. The contact lenses are chosen based on their different basecurves in the posterior and anterior curvature radius as well as itsoptical diameter and multiple peripheral zones to induce changes in thecorneal physiology and anatomy. In certain embodiments, the contact lensexerts pressure on the central zone of the cornea, thereby flatteningthe cornea and taking out dioptric power. In other embodiments, thecontact lens exerts pressure at the periphery of the cornea, therebysteepening the cornea and adding dioptric power. The contact lensesconstantly, gradually, and uniformly change the shape of the cornea toachieve the desired shape and thereby the refractive power needed by thepatient. The contact lenses used in the inventive system are preferablyoff-the-shelf rigid or soft contact lenses that already existcommercially. Preferably the contact lenses are not specificallydesigned for orthokeratology. The contact lenses may be specially madefor the patient being treated, or the contact lenses may be speciallymade for orthokeratology. The wearing of the contact lenses will bedetermined by various factors including the desired change in thecornea, the visual memory of the patient, the patient's age, thepatient's tolerance of the lenses, the duration of the treatment, thepharmaceutical composition prescribed, etc. In certain embodiments, thecontact lenses are worn several hours per day (e.g., 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 hours per day) or all day long for several weeks (2,3, 4, 5, 6, 7, 8, 9, 10 weeks) until the desired changes have been made.In certain embodiments, the contact lenses are worn overnight. Thecontact lenses used in the treatment may be changed over the course ofthe treatment as determined by the ophthalmologist with consultationwith the patient. The present invention may change the dioptric power ofthe cornea by up to 5 Diopters, preferably up to 4 Diopters.

As well as wearing the contact lenses, the patient must also use apharmaceutical composition, preferably eye drops, suitable for deliveryto the eye that allows the cornea to be more readily molded. Thepharmaceutical composition may also stabilize, improve, increase thechange of the corneal curvature, or reduce the incidence of undesiredside effects. In certain embodiments, the composition enhances themechanical stress on the eye exerted by the contact lens over thesurface of the cornea. These eye drops typically contain enzymes suchhyaluronase and/or collagenase, and/or other agents such as carbamide(urea). In certain embodiments, the pharmaceutical composition alsocontains a vehicle such as methylcellulose or polyvinyl alcohol. Theformulation of the eye drops is adjusted depending on various factorssuch as the age of the patient, the degree of change being made in thecornea, the physiology of the patient's cornea, the disease beingtreated, the duration of the treatment, etc. The eye drops may alsocontain other ingredients such as lubricants, vitamins, antibiotics,anti-inflammatory agents, anti-allergies, immunosuppressants,vasoconstrictors, and anesthetics. The eye drops may be in a liquid,spray, or gel form. Typically, the eye drops are administered at leastonce per day. In certain embodiments, the eye drops are administeredonce, twice, three times, four times, or five times per day. In otherembodiments, the eye drops are administered every five minutes, everyfifteen minutes, every half hour, every hour, every two hours, or everythree hours. The use of the eye drops is continued for as long as thepatient wears the contact lenses. The present invention providespharmaceutical compositions to be used as eye drops in the treatmentmethod. The inventive pharmaceutical compositions may also useful incombination with refractive surgery, in treating patients with low ormoderate refractive error, and in preventing presbyopia.

In certain embodiments, the pharmaceutical agents found in the eye dropsare included in the contact lenses. For example, the contact lenses areimpregnated or coated with the agents so that the wearing of the contactlenses provides continuous deliver of the agents. Any of the agentsdescribed herein such as hyaluronidase, collagenase, vehicle,anti-inflammatory, lubricants, antibiotics, etc. may be added to thecontact lenses for time-release delivery of the agent(s). This manner ofdelivering the agents is particularly useful when the contact lenses areworn at night while the patient is sleeping.

The inventive treatment system is useful in treating ophthalmicconditions such as presbyopia, myopia, hyperopia, and astigmatism. Thetreatment system may also be used in treating other diseases involvingrefractive error. Preferably, the inventive system is the first line oftreatment for these conditions. In other embodiments, the patient mayhave already undergone a more traditional treatment such as LASIK orPRK, and the inventive system may be used to further correct anyresidual refractive error remaining after the first procedure. Thisallows correction of any remaining error without an additional surgery.The residual refractive error is commonly due to the lack of an exactmeasurement of the refractive defect before the surgery but can be dueto other causes as described above. Therefore, the best way to correctthe residual error is using a dynamic and interactive technique such asthe inventive method in order to gradually change the curvature of thecornea until the patient finds that his or her visual needs (i.e., thecorneal power is sufficient for the patient's visual needs based on thepatient's visual memory and cerebral accommodation) for near and farvision are met. In certain embodiments, the corneal power is notcorrected perfectly because this may prevent the seeing near or far.Instead, the patient may rely on other compensatory measures to achieveperfect vision under various circumstances, such as low light, fatigue,seeing far away, seeing close up, reading, etc.

In one aspect, the present invention provides a kit containing itemsuseful in treating ophthalmic conditions such as presbyopia using theinventive method. The kit may contain all or some of the following:reservoir for contact lens, solutions for cleaning and/or disinfectingcontact lenses, at least one pair of contact lenses, back-up contactlenses, eye drops as described above, lubricants, eye charts, mirror,and instructions for the patient. Preferably, the items of the kit arepackaged in an ergonomic case which preferably is portable.

In another aspect, the present invention provides software useful to thetreating ophthalmologist, optometrist, nurse, or other health careprofessional. Certain information about the patient is entered into theprogram running on a computer. This information may include name, age,sex, profession, description of visual needs, visual acuity,keratometry, retinoscopy, etc. The operator of the software may then beasked a series of questions (e.g., rigid or soft contact lenses. Fromthe data entered into the program, the software may determine the typeof contact lenses to be used (e.g., soft or hard), the power indiopters, the posterior base curve, the posterior peripheral curvature,the anterior curve, the anterior peripheral curve, diameter of centralzone, and the diameter of the peripheral zone. The software may also beused to determine the composition of the pharmaceutical composition tobe prescribed to the patient and/or the dosing regimen.

Definitions

“Animal”: The term animal, as used herein, refers to humans as well asnon-human animals, including, for example, mammals, birds, reptiles,amphibians, and fish. Preferably, the non-human animal is a mammal(e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, aprimate, or a pig). In certain embodiments, the animal is a human.

“Cerebral accommodation”: Cerebral accommodation refers to any functionsthat control the movements of the muscles involved in theoptical-cerebral-motor system. Cerebral accommodation is necessary tofocus the image in order to see well both near and far objects. Incertain instances, cerebral accommodation refers to the reflex arcs andthe muscle and nervous stimuli that are needed to achieve the propermovements of the body (e.g., head, neck) and eyes in order to see wellnear and far.

“Corneal power”: Corneal power refers to the mathematical valueexpressed in diopters of the corneal refractive power or in millimeterswhen referring to curvature radius. Corneal power refers to themathematical value of refractive power that is needed to meet thedemands of the visual system including visual memory and cerebralaccommodation. To measure the corneal power, it is necessary todetermine the radius of anterior curvature, the corneal thickness, andthe radius of posterior corneal curvature. In most instances, thecorneal power cannot be measured exactly because all the differentanatomical areas contributing to corneal power cannot be measured.Corneal power may also change during the day (e.g., due to fatigue) andfrom day-to-day.

“Induction of change in corneal power” refers to the mathematical changein diopters or in millimeters of curvature radius, of the value of theradius of the anterior corneal curvature that is to be induced toachieve the necessary dioptric power to change the corneal refractionpower and thereby to achieve the near and far vision required by thepatient in each eye.

“Effective amount”: In general, the “effective amount” of an activeagent or a pharmaceutical composition refers to the amount necessary toelicit the desired biological response. As will be appreciated by thoseof ordinary skill in this art, the effective amount of an agent may varydepending on such factors as the desired biological endpoint, the agentbeing delivered, the disease being treated, the subject being treated,etc. The effective amount of hyaluronase in the pharmaceuticalcomposition is the amount necessary to degrade enough hyaluronic acidmolecule to allow for molding of the cornea. The effective amount ofcollagenase in the pharmaceutical composition is the amount necessary todegrade enough collagen to allow for molding of the cornea. Theeffective amount of carbamide in the pharmaceutical composition is theamount necessary to allow for molding of the cornea.

“Molding contact lens”: Molding contact lenses are any contact lensesthat are used with the inventive method and system. The lenses may beparticularly designed for molding the cornea to a shape in someembodiments. However, in other embodiments, the molding contact lensesare not especially designed for the inventive system but are instead offthe shelf contact lenses typically worn by a patient to correct visions.The molding contact lenses may be rigid or soft, permeable ornon-permeable. The molding contact lens are typically made of a plastic,polymer, or glass. In some embodiments, the molding contact lensesinclude pharmaceutical agents helpful in molding the cornea to aparticular shape.

“Optical-cerebral-motor system”: The optical-cerebral-motor systemrefers to the anatomical structures of the body that by interconnections(e.g., nerves) interact to carry out the muscular adjustments of thebody and of the ocular globe to achieve an adequate position and to beable to activate the reflexes, voluntary, and involuntary movementsnecessary for seeing objects near and far. The system may include thevisual cortex, the motor cortex, muscles of the head and neck, musclesof the eye, optic nerves, cranial nerves, and eyes.

“Point of dispersion”: Point of dispersion is the point at whichdivergent rays would intersect if traced backward. The point ofdispersion can also refer to an image of an object or a visual stimulusthat characterizes an optical system.

“Stromal sliding”: Stromal sliding is the displacement of the cornealstroma after any refractive surgery performed on the cornea. Stromalsliding is due to the separation of the lamellae during the cutting orablation of the corneal tissue. This allows the corneal wound to slidethereby flattening or steepening the corneal curvature during thehealing process. Stromal sliding is also an important part of theinventive technique.

“Visual acuity”: Visual acuity refers to the clarity or clearness ofone's vision, a measure of how well a person sees. In certainembodiments, it refers to the Snellen acuity (e.g., 20/20).

“Visual memory”: Visual memory refers to the accumulation of the imagesat the brain that are received through the optical-cerebral-motor systemduring one's lifetime. Visual memory starts to form when the firstimages arrive into the brain during childhood. The brain recognizes andperceives the wavelengths of light as images. The brain organizes allthe images it accumulates and uses this information to react to visualstimuli and recognize objects (e.g., letters of the alphabet). Thevisual memory develops depending on how often certain types of stimuliare in front of the eyes. Developing visual memory may depend onsharpness of the images arriving at the retina or brain, physical andmental development, environmental influences, heredity, etc. The visualmemory forms from images transmitted to the brain with or withoutcorrection (e.g., eyeglasses or contact lenses). Normally, visual memorywill tolerate small discrepancies such as, for example, due to illness,stress, fatigue, etc. Visual memory allows the patient to compensate andcarry on normal activities such as driving, reading, writing, drawing,playing sports, etc. Visual memory is important in the development ofvisual acuity and is used to orchestrate all the body's compensatorymechanisms, such as cerebral accommodation. For example, when the eyecannot transmit good quality images to the brain for a near stimulus,the visual memory reacts and starts to demand visual quality it has cometo expect. The visual memory may turn on certain compensatory mechanismssuch as cerebral accommodation. When the cerebral accommodation cannotcompensate adequately, the patient may need to resort to othercompensatory mechanisms such as squinting, turning up light levels,moving eyes further away or closer, using glasses, etc. For example, inreading a book, if the patient is fatigued, he or she may need to holdthe book closer or turn up the light level in order to read. The cornealpower is preferably adjusted so that the visual images transmitted tothe brain are accepted by visual memory. The patient's own satisfactionand acceptance of the new images is preferably the way the corneal powerhas been corrected by the inventive system to the extent needed byvisual memory.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is an illustration of Gullstrand's model of the eye. This modelis used to calculate the refractive power of the cornea as well as otherparts of the eye. Such a schematic is useful in determining theadjustments to the cornea needed in correcting the patient's vision.

FIG. 2 is an illustration of the Sturm's conoid used to show theformation of an image by a sphero-cylindrical lens.

FIG. 3 is a photograph that shows the differences that exist in thethickness and radius of curvature of the anatomical regions of the eye.

FIG. 4 is a schematic view showing stromal sliding.

FIG. 5 depicts a mathematical model of the eye. The drawing shows thetheoretical measurements needed to calculate corneal power and theocular globe dioptric power. Note that this traditional model of the eyeuses a sphere to present the ocular globe and mathematical constants inthe cornea.

FIG. 6 shows a normal eye. The normal eye is not in fact a sphere. Ithas various anatomical irregularities and differences, and the opticalaxis is off center from the geometric axis.

FIG. 7 shows a small centered contact lens on top of the cornea. Usingthis contact lens, pressure is applied to the central zone of thecornea. The peripheral zone is not touched by the contact lens. Pressureon the central zone of the cornea will flatten the central cornea andlessen the dioptric power of the cornea.

FIG. 8 shows a small centered contact lens on top of the cornea. Thecontact lens is exerting pressure on the peripheral zone of the cornea.The central zone of the cornea is not touched by the contact lens.Pressure on the periphery will steepen the central cornea, therebyadding dioptric power to the cornea.

FIG. 9 shows a larger centered contact lens on top of the cornea. Thecontact lens is applying pressure to the peripheral zone of the cornea.This peripheral pressure will cause the central portion of the cornea tosteepen, thereby adding dioptric power to the cornea.

FIG. 10 shows a larger centered contact lens on top of the cornea. Inthis figure, the contact lens is exerting pressure on the central zoneof the cornea. This pressure on the central zone will flatten the corneaand take out dioptric power from the cornea.

DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS OF THE INVENTION

The present treatment system is based on inducing a change in thecurvature of the cornea (e.g., the anterior radius of the cornea). Thechange allows the patient to see better near and far without the needfor eyeglasses, contact lenses, or other visual aids. The system worksby inducing a compound myopic astigmatism with a vertical axis(horizontal or oblique) according to the visual needs of the patientbeing treated. The system is interactive and depends on input from thepatient on how the treatment is to proceed. This is one of thedifferences between the inventive system and those already known in theart that essentially rely on detailed measurements of aspects of the eyeby an ophthalmologist.

The methods used to induce changes in the anterior radius of the corneainclude wearing molding contact lenses after refractive surgicaltechniques such as LASIK, LASEK, PRK, CK, or other surgical proceduresthat alter the anterior layers of the cornea or the sclera or any changeor alteration in the refractive power of the eye; wearing moldingcontact lenses and using a pharmaceutical composition suitable foradministration to the eye when the refractive error is low to moderate,when the patient has been operated on and the healing process is alreadycomplete, or when the patient has had no surgeries but is suffering frompresbyopia, myopia, hyperopia, astigmatism, or other ophthalmiccondition. The method is a dynamic and interactive technique in that thenormal physiology of the cornea is altered at the same time the visualmemory and cerebral accommodation of the patient is altered to achievethe refractive power of the cornea necessary to achieve the desired nearand far vision of the patient. The inventive method alters the cornea ina gradual, continuous, programmed, and controlled way without producingirreversible changes or undesired complications. In certain embodiments,the method alters the cornea in a uniform manner. In other embodiments,the change induced is not uniform (e.g., in treating astigmatism). Thepatient plays an important role in guiding the treatment to achieve thedesired vision much like a photographer focusing the lens of a camera.

Any patient with a refractive error can be treated using the inventivesystem. Ophthalmic conditions treatable using the inventive systeminclude presbyopia, hyperopia, myopia, astigmatism, and any otherophthalmic condition that can be treated by changing the shape of thecornea. In certain embodiments, the patient suffers or is at risk ofsuffering from presbyopia. Certain patients have had good visions fornear and far vision, have never needed eyeglasses or contact lenses, butcould develop presbyopia with increasing age resulting in diminishednear vision. In other embodiments, the patient is born with a refractivedefect (e.g., a genetic refractive defect), and the patient desires tocorrect the defect in any one of the different distances—near,intermediate, or far. In yet other embodiments, the patient hasundergone surgery to correct a refractive error but a residual defect inrefraction remains in near, far, and/or intermediate vision. In certainembodiments, the patient under 18 years of age is treated for arefractive defect so that when he or she reaches the age of 40 and thesymptoms of presbyopia begin, the changes in the refractive power of thecornea can be minimized and therefore better accepted by the patient(e.g., visual memory, cerebral accommodation) without inconvenience ordiscomfort.

Cerebral accommodation is a natural process. Cerebral accommodation isbased on a function of the brain, specifically the function allowing theimages to form through the visual organ and to execute the muscularactions used to initiate and complete the reflexes that interconnect theoptical and motor systems. Once images are captured by the eye, they aresent to the brain (visual cortex) and stored in visual memory. Thevisual stimuli during the normal development of each individual variesand this is why cerebral accommodation plays such a key role in carryingout functions that the individual apparently carries out unconsciously.The inventive system therefore takes into account cerebral accommodationin the treatment of the patient. The transmission of the unfocused,blurry image becomes very difficult to associate and to interpret withthe other images in visual memory at the onset of presbyopia when theeye and the nervous system are not in sync. As a result the patientrequires the use of eyeglasses. The inventive technique molds the corneato achieve the near and far vision that the patient requires to meet thedemands of the visual system including the visual cortex and visualmemory.

The invention is better understood by considering the Gullstrand's modelof the eye (FIG. 1) and the conoid of Sturm (FIG. 2). As will beappreciated by others of skill in this art, other models of the eye mayalso be used mathematically model the visual system. The model ofGullstrand shows the elements for the calculation of the refractivepower of the cornea in accordance with the present invention using oldand traditional mathematical concepts. This calculation of therefractive power of the cornea is based on the radius of curvature ofthe anterior surface of the cornea, the corneal thickness, and theradius of curvature of the posterior surface of the cornea.

The initial measure of the radius of curvature of the anterior surfaceof the cornea is obtained by keratometer measurements. The measurementis done directly in diopters if the refractive index as determined bythe keratometer is the same as used in the calculation by the treatingphysician. Preferably, the measurement is done in the same units as usedby the treating physician. In addition, it is preferably that allinstruments used in the invention are calibrated together. In certainembodiments, the measurement of the initial radius (R_(i)) is made inmillimeters and then converted to diopters using the following formula:D=[(n−n′)×1.000]/Rwhere D=diopters, n=refractive index of air, n′=refractive index of thecornea, R=radius of curvature of the anterior surface of the cornea,R_(i)=initial radius, and D_(i)=initial diopter.Estimate of the Refraction Defect

The amount of the refractive defect in the eye is measured in thecorneal vertex with the following formula:D _(v) =D _(c)/[1−(×D _(c)/1.000)]where D_(v)=diopters to vertex, and D_(c)=diopters of correction.

Then the final diopters are calculated by the following formula:D _(f) =D _(i) +D _(v)=332/R _(i) +D _(v)where D_(f)=final diopter, D_(i)=initial diopter, R_(i)=initial diopter,and D_(v)=diopters to vertex.Final Radius

The final radius of curvature of the anterior surface of the moldedcornea is calculated in millimeters, instead of diopters, to facilitateuse with different measuring equipment. The final radius is calculatedusing the following formula:R _(f)=332/[(332/R _(i))+D _(v)]where R_(f)=final radius, R_(i)=initial radius, and D_(v)=diopters tovertex.Corneal Thickness

The conical thickness is calculated based on the difference between theradius of curvature of the anterior surface and the radius of curvatureof the interface (the ablation obtained in the anterior stroma).

Radius of Posterior Surface

The radius of curvature of the posterior surface is equal to the finalradius minus the post-surgical stromal thickness (R_(sp)=R_(f)−E_(d)).

The calibration of the optical equipment is based on the Gullstrand'smodel of the eye. When there is a large change in any one of the partsof the eye being measured (e.g., the radius of curvature, the thicknessof the cornea, the index of refraction), it is no longer possible toprecisely measure the refractive power of the cornea in the majority ofautomated optical equipment (e.g., the auto-kerato-refractometer).Consequently, to be able to carry out the exact mathematicalcalculations it is necessary to utilize equipment that actually measuresthe radius of curvature of the anterior surface, the corneal thickness,and the radius of curvature of the posterior surface (e.g., ORBSCAN II,commercially available from Bausch & Lomb Surgical). This type ofequipment, in general, measures the refractive power of the cornea invery large increments (e.g., 0.25 D), which causes errors for thecorrect measurement of the vision of the patient and consequently toobtain the mathematical formula for the calculation of the refractivepower of the cornea that is required to reach the desired near and farvision for the patient.

In the present invention, the induced refractive power of the cornea isconsidered similar to a sphere (myopia) and a myopic cylinder(astigmatism) of 0.100 of diopters to 0.999 of diopters, that is therecommendable range to be able to correct the near vision withoutdiminishing significantly the far vision. Myopic astigmatism is fromsphere −0.100 to −0.999 D. Hyperopic astigmatism is from sphere +0.100to +0.999 D. The cylinder in astigmatism is −0.100 to −0.999. The axisof astigmatism can be 0° to 360°. As will be appreciated by one of skillin this art, the visual quality and visual capacity will also be relatedto pupil diameter.

The entire visual system including the lens, zonule, ciliary muscle,ciliary body, sclera, brain, visual cortex, and visual memory areconsidered in the dynamic and interactive system of the presentinvention. Each of part of the eye plays an important role in vision,and modifications of each of these parts either iatrogenically or byaging causes changes in the vision of the patient.

Once the measurements and calculations above have been measured, thepatient is consulted to determine his or her visual needs both for nearand far vision. This is based on the fact that the patient is the onewho really measures, feels, and relies on his or her refractive power ofthe cornea. The person administering the treatment can then use thisinformation in approaching the mathematical formulae described above.This combined approach guides the treatment of the patient indetermining the steepness or flatness to be induced in the patient'scornea.

To carry out the reshaping of the patient's cornea, the inventive systemcombines the use of molding contact lenses and a pharmaceutical agentsuitable for administration to the eye (e.g., eye drops). In certainembodiments, computer software is used to determine the contact lensesmost suitable for the patient and/or to determine the formulation of thepharmaceutical agent.

The software of the invention prompts the health care professional(e.g., ophthalmologist, optometrist, nurse, etc.) to enter certaininformation about the patient. This information may include name; age;sex; profession; near working distance; tolerance to contact lenses (ifthe patient has used them before), optometric data; visual acuity (e.g.,near, far, with both eyes, each eye separately, corrected, oruncorrected); keratometry; topography; paquimetry (thickness of thecornea); wave front; ray tracing measurements; retinoscopy with normalpupil; refraction with normal pupil; best corrected visual acuity (e.g.,far or near, both eyes or each eye separately); retincoscopy withmydriasis; refraction with mydriasis; best near vision for vision at 45to 55 cm, for Jaeger 3, for Jaeger 4, or for Jaeger 5; etc. Any of theinput data described above may be included or excluded from theprogram's determination of the contact lenses or pharmaceuticalcomposition to be used by the patient. The software may also allow theconversion of keratometry from diopters to millimeters. The user may beprompted to choose a flatter, steeper, or average keratometry. The usermay be asked to choose between soft or hard contact lenses for thepatient. The user may be asked to enter posterior base curve, peripheralposterior curve, anterior curve, and/or anterior peripheral curve. Theuser may also be asked to choose the power. In certain embodiments, thesoftware uses the entered data to determine the contact lenses to beused by the patient. The software may determined soft versus hardcontact lenses, power in diopters, posterior base curve, posteriorperipheral curvature, anterior curve, anterior peripheral curve,diameter central zone, and/or diameter peripheral zone. In certainembodiments, the software will determine the composition of thepharmaceutical composition and/or the dosing regimen for thepharmaceutical composition.

In a certain embodiment, the software begins by prompting the user forthe following patient data: name, age, right eye keratometry, right eyepaquimetry (thickness of cornea), right eye ocular defect, left eyekeratometry, left eye paquimetry (thickness of cornea), left eye oculardefect, and whether the patient has worn contact lenses before. If thepatient has worn contact lenses before, the user is prompted to enterinformation regarding what type of contact lenses they were and whetherthey were comfortable. For the patient who has never worn contactlenses, the user is asked to select the patient's sensitivity level(e.g., high, low, null). After the information is entered, the softwareconfirms that all data has been entered and that the information fallswithin certain ranges. For example, the patient's age must be between 1and 100 years. The right and left eye keratometry must be between 34.09and 55.32 D. The paquimetry of both eyes must be a value between 450 and650 microns. The user is asked to confirm all the entered data to reducethe chance of error. After all the data has been entered, the softwarethen calculates the results using the formula described herein. Thesoftware determines the type or contact lens recommended for the patientand the base curve expressed in millimeters. When the defect is largerthan 2 D, the message “Define lens power depending on patient”. When thekeratometry value of any eye is less than 40 or larger than 48 D, thefollowing message will appear “Define peripheral base curve.”

The inventive method for treating a patient suffering from a disorderinvolving refractive error such as presbyopia includes assessing thepatient (e.g., age, working needs of the patient, eye disease, etc.),prescribing the use of molding contact lenses to induce the neededchanges in the radius of curvature of the anterior surface of thecornea, and prescribing the use of a pharmaceutical composition to beused in conjunction with the contact lenses.

The present system can be used to induce a change in the refractivepower of the cornea by inducing a change in the radius of curvature ofthe anterior surface of cornea with a myopic range (sphere) of −0.25 Dto −0.75 D or with a myopic astigmatism (cylinder) of −0.25 D to −0.75D. By inducing a change in the refractive power of the cornea withmyopia (sphere) greater than 1.00 D or more than 1.00 D in astigmatism(cylinder), the near vision is improved but the far vision diminishes.In certain preferred embodiments, the range for correcting the nearvision without diminishing the far vision substantially is 0.100 D up to0.999 D. To determine the best axis of astigmatism that the patientrequires for near vision, each eye is evaluated separately.

In other embodiments, the change is induced in the refractive power ofthe cornea with a vertical axis of myopic astigmatism (e.g., in the caseof vertical astigmatism with less than 45° with respect to the vertical(90°)).

The inventive method is particularly useful because it allows thetreatment each eye of every patient to be completely personal. Thetreating physician is not limited to the measuring equipment or theavailable eyeglasses or contact lenses in treating the patient's visualerror. Therefore, the precision of the correction is not limited to0.100 D but instead can be performed with a greater degree of precision(e.g., 0.01 D, 0.005 D, 0.001 D, 0.0005 D, or 0.0001 D). The patientguides the treatment according to his or her visual needs. The treatingphysician can stop or alter the treatment as needed.

As described above, the currently existing instruments that are used tomeasure the extent of myopia or astigmatism do not measure the value ofthe radius of curvature of the anterior surface of the cornea, thecorneal thickness, or the radius of curvature of the posterior surfaceof the cornea with the required precision.

The molding contact lenses which are prescribed and worn by the patientexert a mechanical force on the anterior surface of the cornea therebyinducing a change in the refractive power of the cornea. In certainembodiments, the molding contact lenses are hard or rigid moldingcontact lenses. In other embodiments, the molding contact lenses aresoft contact lenses.

Once the molding contact lenses is placed on the eye of the patient, apharmaceutical composition (e.g., eye drops) that allows for molding ofthe cornea is administered to the eye and/or reduce the connectionsbetween the corneal lamellae. The contact lenses and the pharmaceuticalcomposition together produce the change in the refractive power of thecornea. The more frequently the pharmaceutical composition isadministered the more quickly the corneal lamellas will adopt thedesired change in shape. In certain embodiments, the composition isadministered at least every 8 hours. In other embodiments, thecomposition is administered every 6 hours. In certain other embodiments,the composition is administered approximately every 3 hours. In yetother embodiments, the composition is administered approximately everytwo hours. In other embodiments, the composition is administered everyone hour. The composition may be hypertonic (5% to 40%, preferablyapproximately 10, 20, 30, or 40%) or hypotonic (0% to 5%, preferablyapproximately 1, 2, 3, or 4%) depending on the needs of the patient(e.g., working needs, rest hours, sleeping, etc.) A hypertonicpharmaceutical composition (e.g., 40%) is typically used when a fasterresult is desired.

Without wishing to be bound by any particular theory, the inventivesystem is thought to work by the following mechanism. After anyrefractive surgical technique that cause spaces among the stromallamellas either by cuts, resections, or ablations, a stromal slidingwill cause the stroma to slide toward the periphery to correct moremyopic defect or slide toward the center of the cornea to correcthyperopia or presbyopia (see FIG. 4). When molding contact lenses areused in conjunction with a pharmaceutical composition that enhances themechanical force of the contact lenses, the corneal stroma is alteredalong with its anatomical and histological structures. The contactlenses and pharmaceutical composition induce changes in the mechanicalforce of the molecular structure (e.g., lamellas) and induce changes inthe cells and proteins such as collagen and hyaluronic acid found in thecorneal stroma. The surface of the cornea becomes more uniform bymolding the corneal stroma. All healthy corneas have some irregularitiesin the surface as has been shown by isometric tomography and ultrasound.In the inventive system, the quality and clearness of all images (i.e.,visual acuity) is improved by making more uniform the surface of thecornea.

For the calculation of the molding contact lenses the flattestkeratometry is taken. One of skill in this art could also use thesteeper keratometry or an average of both and based on this cornealcurvature make the necessary calculations to flatten or steepen theradius of curvature of the anterior surface of the cornea and thuscorrect the refractive defect of the eye. The base curve of the moldingcontact lens is calculated based on the change in the refractive powerfor each eye separately. The base curve of the molding contact lens iscalculated starting with one to four flatter or steeper diopters, morepreferably one to three flatter or steeper diopters, even morepreferably one to two flatter or steeper diopters, depending on therefractive error that is required. The peripheral base curve depends onthe adaptation of the molding contact lens and is calculated to be 0.5mm of radius greater than the central zone but can vary depending on thedesign. The diameter of the molding contact lens used in the inventivesystem is approximately 8.0 mm to 18.0 mm. These diameters are availablecommerically. In certain embodiments, the molding contact lens is a hardcontact lens with a diameter ranging from 8.0 mm to 12.0 mm. In otherembodiments, the molding contact lens is a soft contact lens with adiameter ranging from 13.0 mm to 15.0 mm. Soft contact lenses may coverthe entire cornea and go from sclera to sclera. In certain embodiments,the molding contact lens is a combination of hard and soft materials. Itmay be hard in the middle out to approximately 12.0 mm, 13.0 mm, 14.0mm, or 15.0 mm, and then soft in the periphery out to 16.0 mm, 17.0 mm,and 18.0 mm. A larger contact lens, preferably a soft contact lens, maybe used at night as a molding contact lens. The power of the moldingcontact lenses is determined to the nearest possible refractive powerthat the patient requires to see comfortably. During the adaptationprocess with the molding contact lenses, if the vision is not adequatefor the needs of the patient, the patient is prescribed eyeglasses whilethe patient is undergoing treatment.

As the cornea is being adapted or has been adapted, various optometricmeasurements are optionally repeated to confirm that the treatment isprogressing as planned and is adequate. Such measurements may includevisual acuity for near and far vision, the distance to see small print(J-3 to J-4) (e.g., print in a newspaper or magazine) satisfactorily,orthotypes, keratometry measurements, objective and subjectiveretinoscopy, diagram of the adaptation of the molding contact lens,movement of the molding contact lens, and comfort of the molding contactlens. After the measurements are taken, changes are made to thetreatment program based on these measurements. Changes in the moldingcontact lenses and/or in the pharmaceutical compositions can be made toinduce the desired refractive power in the cornea over the followingweeks. In certain preferred embodiments, weekly periodic revisions areperformed during the first 8 weeks after beginning treatment. In certainembodiments, if the patient has not undergone refractive surgery, thenthe pharmaceutical composition for administration to the eye should beprescribed.

The molding contact lenses used in the inventive system may be hard orsoft. If a soft molding contact lens, a more positive or negativecurvature is induce in the cornea, and the discomfort in the patient'seyes will diminish as he or she adapts to the contact lenses. If a hardmolding contact lens is used, more mechanical pressure will be exertedon the cornea. In certain preferred embodiments, the contact lenses aregas permeable.

The pharmaceutical composition used in the inventive system includesagents that help to induce changes in the corneal lamellas, collagenfibers, hyaluronic acid, and the percentage of corneal hydration. Otheraspects of the anatomy, histology, and physiology of the cornea may alsobe affected by the agents in the pharmaceutical composition. In certainembodiments, the composition may be hypertonic or hypotonic to inducechanges in the percentage of corneal hydration. In other embodiments,the composition is used to change the sustentation forces of themolecular structure of the cornea (e.g., lamellas) and in this way moldthe stroma to the desired curvature. In certain embodiments, the agentsused in the pharmaceutical composition have been approved for use inhumans by a regulatory agency such as the U.S. Food and DrugAdministration (FDA) or an analogous foreign regulatory body.Preferably, the agents are approved for use in the eye.

In certain embodiments, the composition contains the enzymehyaluronidase which is known to break down hyaluronic acid, whichfunctions like a cement among the corneal lamellas. Hyaluronidase is anenzyme that degraded mucopolysaccharides by catalyzing the hydrolysis ofthe one to four linkages in hyaluronic acid, chondroitin, andchondroitin 4 sulfates A & C. Mucopolysaccharide is one of theintracellular ground substances (cement or glue) of the stroma, theconnective-type tissue of the middle layer of the cornea. The shape ofthe cornea is largely dependent on the arrangement of collagen fibrilsin the stromal layers of the cornea and on the arrangement of themucopolysaccharides layers between these fibrils. Hyaluronidase breaksdown the mucopolysaccharide chains when released into the cornea. Thestroma of the cornea is thereby softened making it more amenable toreshaping by a molding contact lens.

Hyaluronidase may be obtained from a variety of natural sources fromwhich the enzyme can be purified to at least 90% purity, at least 95%purity, at least 96% purity, at least 97% purity, at least 98% purity,or at least 99% purity. Natural sources include bovine (bull) testes,ovine (sheep) testes, and bacteria (Streptomyces). In certainembodiments, hyaluronidase is commercially available. For example, oneform of hyalouronidase is available under the trade name WYDASE® (WyethLaboratories, Inc., Philadelphia, Pa.). The WYDASE® hyaluronidase is apreparation of highly purified bovine testicular hyaluronidase. Thehyaluronidase enzyme may be supplied as a lyophilized powder. The powdercan be reconstituted using phosphate buffer-saline solution. Typicalproportions include approximately 150 USP units of hyaluronidase per 1milliliter. In certain embodiments, the hyaluronidase is prepared usingrecombinant DNA technology. The hyaluronidase may be a modified version,e.g., a cleaved form, chemically modified, or genetically modified.

In certain embodiments, the concentration (weight percent) ofhyaluronidase in the pharmaceutical composition ranges from 0.01% to10%, or 0.1% to 7%, or 0.1% to 5%, or 1% to 5%. Increasing theconcentration of hyaluronidase increases the ability of the contact lensto mold the cornea. In addition, the use of a vehicle such as a polymer(e.g., methylcellulose, polyvinyl alcohol, cellulose, etc.) in thecomposition allows the hyaluronidase to work on the cornea longer thanwithout a vehicle.

It has been discovered that an effective amount of hyaluronidase forsoftening a cornea in a mammal is between approximately 50 units ofenzyme per milligram of substrate (i.e., the mucopolysaccharide of thecornea) to approximately 5,000 units per milligram of substrate.Preferably, the effective amount is between 100 and 1,500 units permilligram of substrate. Higher doses may be administered to reduce thenumber of administrations necessary.

Other enzymes which may be included in the composition to soften thecornea include chondroitinase ABC, chondroitinase AC, keratanse, andstromelysin, which have been shown to work on various proteoglycancomponents of the cornea.

In certain embodiments, the composition contains the enzyme collagenasewhich is known to break down collagen, which functions as anextracellular matrix protein. In certain embodiments, the collagenase isprepared using recombinant DNA technology. In other embodiments, thecollagenase is purified from a natural source. The collagenase may be amodified version, e.g., a cleaved form, chemically modified, orgenetically modified. Other enzymes which break down the collagencomponents of the cornea include matrix metalloproteinase 1(interstitial collagenase) and matrix metalloproteinase 2 (gelatinase).These enzymes may be used individually or in combination with otherenzymes such as those that break down the proteoglycan component of thecornea. See U.S. Pat. Nos. 5,626,865 and 6,132,735, issued May 6, 1997and Oct. 17, 2000, respectively, each of which is incorporated herein byreference. In certain embodiments, the pharmaceutical compositioncontains a combination of hyaluronidase and collagenase.

In certain embodiments, the concentration (weight percent) ofcollagenase in the pharmaceutical composition ranges from 0.01% to 10%,or 0.1% to 7%, or 0.1% to 6%, or 1% to 5%. Increasing the concentrationof collagenase increases the ability of the contact lens to mold thecornea. In addition, the use of a vehicle such as a polymer (e.g.,methylcellulose, polyvinyl alcohol, cellulose, etc.) in the compositionallows the collagensase to work on the cornea longer than without avehicle present.

In another embodiment, enzymes endogenous to the eye of the patient areused to soften the cornea. These endogenous enzymes are activated tobegin the softening process. Metalloproteinzases are activated by theadministration of interleukin-1α, tumor necrosis factor, monosodiumurate monohydrate, 4-amino phenylmercuric acetate, human serum amyloidA, human B₂ microglobin, and copper chloride. See U.S. Pat. Nos.5,626,865 and 6,132,735, issued May 6, 1997 and Oct. 17, 2000,respectively, each of which is incorporated herein by reference.

In certain embodiments, the composition contains the carbamide (urea).In certain embodiments, the carbamide is obtained from commercialsources. In other embodiments, the carbamide is purified from a naturalsource. The carbamide may be a derivative of carbamide or a salt ofcarbamide.

The pharmaceutical composition may also contain enzymes that degradeother sugars or proteins found in the cornea. In certain embodiments,the enzymes act to level the unions of the lamellas in the cornea. Inother embodiments, the pharmaceutical composition alters the stromalhydration of the cornea or the corneal thickness. In other embodiments,an agent known to change the sustentation forces of the molecularstructure of the cornea (e.g., corneal lamellas) is included in thepharmaceutical composition.

The pharmaceutical composition may contain other agents useful in theinventive procedure. In certain embodiments, the pharmaceuticalcomposition contains an anesthetics used to reduce the irritation of themolding contact lens on the cornea. Examples of anesthetics includebenzocaine, bupivacaine, cocaine, etidocaine, lidocaine, mepivacaine,pramoxine, prilocaine, chloroprocaine, procaine, proparacaine,ropicaine, and tetracaine. In other embodiments, the pharmaceuticalcomposition includes a anti-inflammatory agent such as a steroid or anon-steroidal anti-inflammatory agent. Example of anti-inflammatoryagents include aspirin, acetaminophen, indomethacin, sulfasalazine,olsalazine, sodium salicylate, choline magnesium trisalicylate,salsalate, diflunisal, salicylsalicylic acid, sulindac, etodolac,tolmetin, diclofenac, ketorolac, ibuprofen, naproxen, flurbiprofen,ketoprofen, fenoprofen, suprofen, oxaproxin, mefenamic acid,meclofenamic acid, oxicams, piroxicam, tenoxicam, pyrazolidinediones,phenylbutazone, oxyphenthatrazone, pheniramine, antazoline, nabumetone,COX-2 inhibitors (Celebrex), apazone, nimesulide, and zileuton.Glucocorticoids such as hydrocortisone, prednisolone, fluorometholone,and dexamethasone may also be used as anti-inflammatory agents. In stillother embodiments, the pharmaceutical composition includes a lubricant.These agents are included to improve the comfort of the patient duringthe treatment. One of skill in this art based on the individual patientdetermines the composition of the eye drops being prescribed for thepatient.

In certain other embodiments, the pharmaceutical composition includesanti-microbial agents such as anti-bacterial, anti-viral, and/oranti-fungal agents. Exemplary anti-microbial agents include bacitracinzinc, chloramphenicol, chlorotetracycline, ciprofloxacin, erythromycin,gentamicin, norfloxacin, sulfacetamide, sulfisoxazole, polymyxin B,tetracycline, tobramycin, idoxuridine, trifluridine, vidarabine,acyclovir, foscarnet, ganciclovir, natamycin, amphotericin B,clotrimazole, econazole, fluconazole, ketoconazole, miconazole,flucytosine, clindamycin, pyrimethamine, folinic acid, sulfadiazine, andtrimethoprim-sulfamethoxazole.

The pharmaceutical composition may also include vasoconstrictors.Vasoconstrictors may include dipivefrin (propine), epinephrine,phenylephrine, apraclonidine, cocaine, hydroxyamphetamine, naphazoline,tetrahydrozoline, dapiprazole, betaxolol, carteolol, levobunolol,metipranolol, and timolol.

The pharmaceutical composition may also include vitamins or othernutrients such as vitamin A, vitamin B₁, vitamin B₆, vitamin B₁₂,vitamin C (ascorbic acid), vitamin E, vitamin K, and zinc.

The pharmaceutical composition may be provided in any form suitable foradministration to the eye. For example, the pharmaceutical compositionmay be in the form of eyedrops, a semisolid gel, or a spray. In certainembodiments, the molding contact lenses are impregnated with the agentsnecessary to mold the stroma. In this manner, the agents can bedelivered to the cornea continuously and in a time-release manner as thepatient is wearing the contact lenses.

An exemplary pharmaceutical composition of the invention may include5-10% anesthetic, 10-20% antibiotic, 10-20% anti-inflammatory agent,20-30% anti-allergic agent, 20-30% vitamin A, 2-6% hyaluronadase, 3-5%carbamide (urea), 2-5% cytokinase, and 10-20% vasoconstrictor. Theseagents may be combined in a hyper- or hypotonic solution. Thecomposition may also include a vehicle such as a polymermethylcellulose, cellulose, polyvinylalcohol, polyethylene glycol, etc.)The agents may be administered in combination or separately. As will beappreciated by one of skill in this art, one or more of the agents maybe removed from the pharmaceutical composition as determined by thetreating physician. Also as will be appreciated by one of skill in thisart, various substitutions may be made for the agents in thepharmaceutical composition. For example, different broad spectrumantibiotics may be used depending on such factors as allergies of thepatient, costs, likely organisms, etc. In addition, various anesthetics,anti-inflammatory agents, vasoconstrictors, anti-allergic agent, andcytokinase may be used.

In certain embodiments, the molding contact lenses and thepharmaceutical composition are provided in a kit. The kit may optionallyinclude lubricating eyedrops, cleaning solutions for the contact lenses,a contact lens carrying case, an extra pair of contact lenses, andinstructions for wearing the contact lenses and using the pharmaceuticalcomposition.

With all the elements considered above, the mathematical formulae forcorrecting presbyopia with the present inventive method are as follows:R _(f)=[332/(332/R _(i) +D _(v))]+R_((sphere and cylinder of visual memory))D _(f) =D _(i) +D _(v)=(332/R _(i))+D _(v) +D_((sphere and cylinder of visual memory))Where R_(f), R_(i), D_(f), D_(i), and D_(v) are as previously defined.If should be born in mind that the calculations for the molding contactlens prescription can be performed by a computer programmed with theformula described herein.

In patients with presbyopia and who require refractive surgery, it isnecessary to induce the changes in the cornea suggested by themathematical formula of compound myopic astigmatism with a vertical axis(or horizontal or oblique) so that the patient's visual system(including visual memory) begins to accept the new images and togetherwith cerebral accommodation train and educate the patient to change hisor her habits for near and far vision.

Once the desired endpoint has been achieved using the inventive system,the use of the molding contact lenses and the pharmaceutical compositionis discontinued. The treatment may be repeated if the patient's visionor visual needs change over time. For example, if presbyopia increases,re-treatment may be necessary. Or if the patient changes work habits,re-treatment may be necessary. Aging may also cause changes in visionrequiring re-treatment. As already mentioned, the patient guides thetreatment to achieve the vision desired. Consequently, based on theinformation provided by the patient and the results obtained inmeasuring the refractive power of the cornea, if the patient desires, iffar vision is better than near vision, then the radius of curvature ofthe anterior corneal surface (both in sphere and in cylinder) needs tobe steepened. If the patient has better near vision than far vision, theradius of curvature of the anterior corneal surface needs to beflattened. If the image is distorted, a change in astigmatism (cylinder)axis is induced until vision improves.

With each evaluation, the decision is made whether to continue with thesame molding contact lens or whether a new contact lens should be used.In addition, the same decision must be made with regard to thepharmaceutical composition being used with the molding contact lenses.

Another important aspect of the inventive method is that it can be usedto change the refractive power of the cornea to improve upon the resultof any refractive surgery or other technique to correct refractiveerrors. In patients recently having undergone a refractive surgery, therefractive power of the cornea can be tuned up or improved. As describedabove, in almost all refractive surgeries there remains a residualrefractive error that can be corrected or improved to reach the visionthat the patient requires. During the first four weeks after refractivesurgery (which is the approximate time it takes for the corneal wound tocompletely heal), changes in the refractive power of the cornea can beinduced. In certain embodiments, the inventive treatment is started 24hours, 48 hours, 73 hours, or one week post surgery. External pressureon the cornea caused by a molding contact lens can change the radius ofcurvature of the anterior surface of the cornea to improve the patient'svision and fix or reduce any refractive errors left after the refractivesurgery. Since any residual defects in refraction can be corrected usingthe inventive technique, refractive surgeries are complemented by theinventive technique. In certain circumstances, the inventive techniquebecomes an obligatory complement to refractive surgery.

In FIG. 2, Sturm's conoid is shown which mathematically speaking showsthe circle of less confusion produced by a sphero-cylindrical lens(e.g., the cornea in the human eye), which is the point in which all thelight beams cross through. The Sturm's conoid considers thesphero-cylindrical lens as a smooth and uniform surface as if it wasmade of glass or plastic.

Ophthalmologists continue to refer to the compounded myopic astigmatismas an incorrect solution for the correction of presbyopia because theythink there are going to be producing two images at the level of theretina and therefore the patient cannot see well with the myopia andastigmatism that is to be induced. The ophthalmologist and theoptometrist also performs the measurements at the base of the two planeof the Sturm's conoid and in the circle of less confusion. However, suchan interpretation should be made in a different way which involves oneof advantages of the inventive system. The light beams that form anyimage at the level of the retina can be interpreted for para-axialoptics which consists of considering the measurement of a small centralzone of the cornea and in the apex or axial-axis, including only thelight beams near the central beam, the so-called power axis, and cannotpredict aberrations in the images except astigmatism and refractiveerrors as myopia. The calculations of the para-axial optics arerelatively easy to do and can be done by hand, with a calculator, orwith a computer. Also, the calculations are performed based on geometricoptics, which have the limitation that it does not consider the light asa wave but rather considers the propagation of light as a beam (i.e., astraight line in a uniform medium with a constant refractive index). Themethod for the calculation of the geometric optics consists of tracingthe beams and typically involves using a computer programmed to performsuch calculations. The most important, useful, and fundamental theory isthat which incorporates optics and physics. Such a theory takes intoaccount the fact that light is a wave. This theory predicts theinterference of the wave and the diffraction (when the wave crossessurfaces of different radii, thicknesses, and/or refractive indexes likethe cornea, lens, and other elements of the eye). The calculations ofthe optics using this approach are more difficult. Nevertheless, thisapproach still does not contemplate the irregularities of the retina andthe differences in radius and thickness of each element that intervenesand differences in the refractive indexes in each eye separately.Therefore, this calculation is also not perfect.

With the inventive technique, the disadvantages described above can beminimized or eliminated because this inventive system takes into accountthe visual memory and the cerebral accommodation of the particularpatient, and the point spread function (PSF) in the retina. As is shownin the isometric topography maps in FIG. 3 (Rabinowitz et al., ColorAtlas of Corneal Topography, Interpreting Videokeratography, Igaku-ShoinMedical Publishers, Inc., p. 65; incorporated herein by reference), boththe anterior and posterior surfaces of the cornea have irregularsurfaces for which it is only possible to use the circle of lessconfusion approach to the best nitid possible. The anterior surface ofthe cornea becomes more uniform through the inventive system. In makingthe anterior surface of the cornea more uniform and inducing changes inthe refractive power of the cornea, the inventive system is guided bythe visual needs and visual memory of the patient for both near and farvision.

As described supra, all the surfaces of the cornea are different intheir radii of curvatures and thicknesses. The circle of less confusionand the point spread function in the retina is blurrier than it istypically calculated. The reason why certain individuals have not neededeyeglasses or contact lenses before is simply due to the fact that theirrefractive error is very low, e.g., myopia of 0.690 diopters andastigmatism of 0.712 diopters (actual measurements would be myopia of0.50 D and astigmatism of 0.75 D). The brain with the visual memory andcerebral accommodation including the optic-cerebral-motor system cancompensate for these small refractive defects with the muscles and theareas of the eye that permit the proper focus or accommodation of thedefect in refraction.

The circle of less confusion that is found in the retina of the humaneye does not correspond to a completely uniform circle and is notspherical in its circumference. In addition, the anatomicalirregularities of the cornea produce an infinite number of very smallbut different focal points that are impossible to calculate. As isappreciated by ophthalmologist and optometrists, this is complicatedeven further when one realizes that these small irregularities are foundin each anatomical structure of the eye.

It should be noted that during a typical LASIK surgery the corneal diskis lifted and the laser beam is applied to produce an ablation. In othersurgical techniques that involve cuts or stromal ablations like theLASIK technique, the corneal disk is allowed to slide into the resectedstromal space. The inventive technique makes use of stromal sliding. Thepharmaceutical composition administered to the eye allows or preferablyenhances the stromal sliding, which allows the cornea to steepen orflatten by the pressure exerted by the molding contact lens. Only whenthe inventive technique is used after a refractive surgery can thestromal sliding be observed. The stromal sliding is produced in allsurfaces of the keratectomy where only tenth of microns or microns areneeded to the correct the residual refractive defect left by thesurgery. The inventive system allows vision to reach the optimum forboth eyes, e.g., in the myopic sphere of 0.567 D and in the myopicastigmatism 0.682 D, with an axis of 122.5°.

The corneal disk is displaced toward the periphery to correct moremyopia by flattening the radius of curvature of the anterior surface ofthe cornea or is displaced toward the center of the cornea to improvehyperopia or presbyopia by steepening the radius of curvature of theanterior surface of the cornea (see “Cirugia Refractiva de la Cornea”,Instituto Barraquer de America, Bogota, Colombia, 1999, P. 171;incorporated herein by reference), The formula for the stromal slidingis already developed in “Cirugia Refractiva de la Cornea”, InstitutoBarraquer de America, Bogota, Colombia, 1999, p. 171.

Other Embodiments

The foregoing has been a description of certain non-limiting preferredembodiments of the invention. Those of ordinary skill in the art willappreciate that various changes and modifications to this descriptionmay be made without departing from the spirit or scope of the presentinvention, as defined in the following claims.

What is claimed is:
 1. A method for treating an ophthalmic condition,the method comprising steps of: providing a contact lens; providing eyedrops comprising an effective amount of hyaluronidase and collagenase,wherein the collagenase is not matrix metalloproteinase 1 or matrixmetalloproteinase 2; applying the contact lens to an eye of a patientsuffering from the ophthalmic condition; and applying the eye drops tothe eye of the patient; wherein the treatment corrects the patient'svision, and the treatment results in corrected vision for at least 6months.
 2. The method of claim 1, wherein the contact lens is anextended wear contact lens.
 3. The method of claim 1, wherein thecontact lens is a gas permeable contact lens.
 4. The method of claim 1,wherein the contact lens is a molding contact lens.
 5. The method ofclaim 1, wherein the treatment induces a change in the shape of thecornea.
 6. The method of claim 1, wherein the treatment induces a changein the physiology and anatomy of the cornea by changing the radius ofcurvature of the anterior surface of the eye.
 7. The method of claim 1,wherein the eye drops further comprise at least one agent selected fromthe group consisting of enzymes, anesthetics, vitamins, zinc,antibiotics, anti-allergic agents, carbamide, cytokinases,vasoconstrictors, anti-viral agents, anti-fungal agents,anti-inflammatory agents, and lubricants.
 8. The method of claim 1,wherein the eye drops further comprise a polymer.
 9. The method of claim8, wherein the polymer is selected from the group consisting ofmethylcellulose, cellulose, polyvinyl alcohol, and polyethylene glycol.10. The method of claim 1, wherein the eye drops are hypertonic.
 11. Themethod of claim 1, wherein the eye drops are hypotonic.
 12. The methodof claim 1, wherein the eye drops comprise about 0.01% to about 10%(weight percent) hyaluronidase, and about 0.01% to about 10% (weightpercent) collagenase.
 13. The method of claim 1, wherein the treatmentresults in the correction of up to 3 diopters of refractive errorwithout surgery.
 14. The method of claim 1, wherein the treatmentresults in the correction of up to 4 diopters of refractive errorwithout surgery.
 15. The method of claim 1, wherein the treatmentresults in the correction of up to 5 diopters of refractive errorwithout surgery.
 16. The method of claim 1, whereby the treatmentresults in corrected vision for at least 1 year.
 17. The method of claim1, wherein the eye drops are in the form of a liquid.
 18. The method ofclaim 1, wherein the eye drops are in the form of a gel.
 19. The methodof claim 6, wherein the change is not uniform.
 20. The method of claim1, wherein the ophthalmic condition is myopia.
 21. The method of claim1, wherein the ophthalmic condition is hyperopia.
 22. The method ofclaim 1, wherein the ophthalmic condition is presbyopia.
 23. The methodof claim 1, wherein the ophthalmic condition is astigmatism.
 24. Themethod of claim 1, wherein the ophthalmic condition is associated withan error in refraction of the eye.